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A Phase II Clinical Trial of Epirubicin Plus Cyclophosphamide Followed by Docetaxel Plus Trastuzumab and Bevacizumab Given as Neoadjuvant Therapy for HER2-Positive Locally Advanced Breast Cancer or Given as Adjuvant Therapy for HER2-Positive Pathologic Stage III Breast Cancer

Phase 2
18 Years
Open (Enrolling)
Breast Cancer

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Trial Information

A Phase II Clinical Trial of Epirubicin Plus Cyclophosphamide Followed by Docetaxel Plus Trastuzumab and Bevacizumab Given as Neoadjuvant Therapy for HER2-Positive Locally Advanced Breast Cancer or Given as Adjuvant Therapy for HER2-Positive Pathologic Stage III Breast Cancer

NSABP FB-5 is a Phase II study for women with HER2-positive invasive breast cancer
evaluating a regimen of epirubicin plus cyclophosphamide followed by docetaxel plus
trastuzumab and bevacizumab in two patient cohorts:

- Cohort A: Women with unresected locally advanced breast cancer (clinical Stage IIIA,

- Cohort B: Women with resected pN2 or pN3 (pathologic Stage III) breast cancer.

The primary aims of the study are to determine the rate of cardiac events for all patients
and the pCR rate in the breast and axillary lymph nodes for Cohort A. Cardiac events will
be defined as NYHA Class III/IV congestive heart failure and cardiac death. For Cohort A,
secondary aims of the study include determining the rate of pCR in the breast and the cCR
rate following the neoadjuvant therapy. The secondary aims also include determining the
value of the regimen in improving 5-year RFS and 5-year OS and determining the non-cardiac
toxicities of the regimen in all patients.

Patients in Cohort A will receive neoadjuvant therapy consisting of epirubicin plus
cyclophosphamide (EC) every 21 days for 4 cycles plus bevacizumab given on Day 1 of Cycle 4
only, followed by docetaxel every 21 days for 4 cycles plus bevacizumab every 21 days for
the initial 3 cycles. Patients will also receive weekly trastuzumab beginning with the
first cycle of docetaxel and continuing until 1-7 days before surgery. Patients will then
have breast surgery (lumpectomy or mastectomy) with axillary staging. Approximately 4-6
weeks following surgery, bevacizumab and trastuzumab will resume and continue every 3 weeks
for 13 doses to complete one year of targeted therapy.

Patients in Cohort B will receive adjuvant therapy consisting of EC every 21 days for 4
cycles followed by docetaxel every 21 days for 4 cycles. Beginning with the first cycle of
docetaxel, patients will also receive bevacizumab every 21 days for 4 cycles and weekly
trastuzumab until 3 weeks after the last docetaxel dose. Beginning 3 weeks after the last
dose of docetaxel, both bevacizumab and trastuzumab will then be given every 3 weeks for 13
doses to complete 1 year of targeted therapy.

Cardiac monitoring will be conducted for both cohorts. For Cohort A, LVEF assessments will
be conducted at baseline, post-EC, 2-4 weeks following surgery (about 6 months from study
entry), and 9, 12, 15, and 18 months from study entry. For Cohort B, LVEF assessments will
be conducted at baseline, post-EC, and 6, 9, 12, 15, and 18 months from study entry. The
preferred method for LVEF assessment is 2-D echocardiogram; however, LVEF assessment by MUGA
scan is permitted.

Patient follow-up will continue for 5 years following study entry.

The FB-5 sample size is 105 patients.

Inclusion Criteria:

Conditions for eligibility for patients with LABC (Cohort A):

- The diagnosis of invasive adenocarcinoma of the breast must have been made by core
needle biopsy or limited incisional biopsy.

- Patients must have clinical Stage IIIA, IIIB, or IIIC disease with a mass in the
breast or axilla that is greater than or equal to 2.0 cm measured by clinical exam,
unless the patient has inflammatory breast carcinoma, in which case measurable
disease is not required.

Conditions for eligibility for patients with resected Stage III breast cancer (Cohort B)

- Patients must have undergone either a total mastectomy or a lumpectomy.

- Patients must have completed one of the following procedures for evaluation of
pathologic nodal status.

- Sentinel lymphadenectomy followed by removal of additional non-sentinel lymph
nodes, or

- Axillary lymphadenectomy without SN isolation procedure.

- The interval between the last surgery (for breast cancer treatment or staging) and
study entry must be no more than 84 days.

- By pathologic evaluation, ipsilateral nodes must be pN2 or pN3.

- For patients who undergo lumpectomy, the margins of the resected specimen must be
histologically free of invasive tumor and DCIS as determined by the local
pathologist. If pathologic examination demonstrates tumor at the line of resection,
additional operative procedures may be performed to obtain clear margins. If tumor
is still present at the resected margin after re-excision(s), the patient must
undergo total mastectomy to be eligible. (Patients with margins positive for LCIS
are eligible without additional resection.)

- For patients who undergo mastectomy, margins must be free of gross residual tumor.
Patients with microscopic positive margins are eligible.

Conditions for patient eligibility (ALL patients)

- The patient must have consented to participate and must have signed and dated an
IRB-approved consent form that conforms to federal and institutional guidelines.

- Patients must be female.

- The patient must be greater than or equal to 18 years old.

- The patient's ECOG performance status must be 0 or 1.

- The tumor must be invasive adenocarcinoma of the breast on histologic examination.

- The breast cancer must be determined to be HER2-positive prior to study entry.
Assays performed using FISH require gene amplification. Assays using IHC require a
strongly positive (3+) staining score.

- At the time of study entry, blood counts must meet the following criteria:

- Absolute neutrophil count (ANC) must be greater than/equal to 1200/mm3.

- Platelet count must be greater than/equal to 100,000/mm3.

- Hemoglobin must be greater than/equal to 10 g/dL.

- The following criteria for evidence of adequate hepatic function must be met:

- total bilirubin must be less than/equal to ULN for the lab unless the patient
has a grade 1 bilirubin elevation (greater than ULN to 1.5 x ULN) due to
Gilbert's disease or similar syndrome involving slow conjugation of bilirubin;

- alkaline phosphatase must be less than 2.5 x ULN for the lab; and

- AST must be less than/equal to 1.5 x ULN for the lab.

- Alkaline phosphatase and AST may not both be greater than the ULN. For example,
if the alkaline phosphatase is greater than the ULN but less than/equal to 2.5 x
ULN, then the AST must be less than/equal to the ULN. If the AST is greater than
the ULN but less than/equal to 1.5 x ULN, then the alkaline phosphatase must be
less than/equal to ULN.

- Patients with AST or alkaline phosphatase greater than ULN are eligible for inclusion
in the study if liver imaging (CT, MRI, or PET scan) does not demonstrate metastatic
disease, and has adequate hepatic function.

- Patients with either skeletal pain or alkaline phosphatase that is greater than ULN
but less than/equal to 2.5 x ULN are eligible for inclusion in the study if a bone
scan or PET scan does not demonstrate metastatic disease. Patients with suspicious
findings on bone scan or PET scan are eligible if suspicious findings are confirmed
as benign by x-ray, MRI, or biopsy.

- Serum creatinine less than/equal to ULN for the lab.

- Urine protein/creatinine (UPC) ratio must be less than 1.0.

- All patients must have their LVEF assessed by 2-D echocardiogram within 3 months
prior to study entry. (MUGA scan may be substituted for 2-D echocardiogram based on
institutional preferences.) The LVEF must be greater than/equal to 55% regardless of
the institution's LLN.

- Note: Since the pre-entry LVEF serves as the baseline for comparing subsequent LVEF
assessments to determine if trastuzumab and bevacizumab therapy can be administered,
it is critical that this baseline study be an accurate assessment of the patient's
LVEF. If the baseline LVEF is greater than 65%, the investigator is encouraged to
have the accuracy of the initial LVEF result confirmed and to consider repeating the
study if the accuracy is uncertain.

Exclusion Criteria:

Conditions for patient ineligibility (Cohort A)

- FNA alone to diagnose the primary tumor.

- Surgical axillary staging procedure prior to study entry. (Procedures that are
permitted include: 1) FNA or core biopsy of an axillary node for any patient, and 2)
although not recommended, a pre-neoadjuvant therapy SN biopsy for patients with
clinically negative axillary nodes.

Condition for patient ineligibility (Cohort B)

• Breast reconstruction using tissue expanders or implants at the time of mastectomy.

Conditions for patient ineligibility (ALL patients)

- Definitive clinical or radiologic evidence of metastatic disease.

- Synchronous bilateral invasive breast cancer.

- History of ipsilateral or contralateral invasive breast cancer regardless of
treatment or ipsilateral DCIS treated with RT.

- History of non-breast malignancies within the 5 years prior to study entry. Patients
with the following cancers are eligible if diagnosed and treated within the previous
5 years: carcinoma in situ of the cervix, carcinoma in situ of the colon, melanoma in
situ, and basal cell and squamous cell carcinoma of the skin.

- Prior therapy with anthracyclines, taxanes, trastuzumab, or bevacizumab for any

- Treatment including RT, chemotherapy, and/or targeted therapy, administered for the
currently diagnosed breast cancer prior to study entry.

- Continued therapy with any hormonal agent such as raloxifene, tamoxifen, or other
SERM. (Patients are eligible if these medications are discontinued prior to study

- Any sex hormonal therapy, e.g., birth control pills, ovarian hormone replacement
therapy, etc. These patients are eligible if this therapy is discontinued prior to
study entry. (Women of reproductive potential must agree to use an effective
non-hormonal method of contraception during study therapy and for at least 6 months
after completion of targeted therapy.)

- Cardiac disease that would preclude the use of the drugs included in the FB-5
treatment regimen. This includes but is not confined to:

- Active cardiac disease: angina pectoris that requires the use of anti-anginal
medication; ventricular arrhythmias except for benign premature ventricular
contractions controlled by medication; supraventricular and nodal arrhythmias
requiring a pacemaker or not controlled with medication; conduction abnormality
requiring a pacemaker; and clinically significant valvular disease.

- History of cardiac disease: myocardial infarction documented by elevated cardiac
enzymes or persistent regional wall abnormalities on assessment of LV function;
documented CHF; or documented cardiomyopathy.

- Uncontrolled hypertension defined as systolic BP greater than 150 mmHg or diastolic
BP greater han 90 mmHg, with or without anti-hypertensive medication. Patients with
initial BP elevations are eligible if initiation or adjustment of BP medication
lowers pressure to meet entry criteria.

- History of hypertensive crisis or hypertensive encephalopathy.

- History of TIA or CVA.

- History of other arterial thrombotic event within 12 months before study entry.

- Symptomatic peripheral vascular disease.

- Any significant bleeding within 6 months before study entry, exclusive of menorrhagia
in premenopausal women.

- Serious or non-healing wound, skin ulcers, or bone fracture.

- Gastroduodenal ulcer(s) determined by endoscopy to be active.

- History of GI perforation, abdominal fistulae, or intra-abdominal abscess.

- Anticipation of need for major surgical procedures (other than the breast surgery
required for patients in Cohort A) during study therapy and for at least 3 months
following completion of bevacizumab.

- Known bleeding diathesis, coagulopathy, or requirement for therapeutic doses of

- Other nonmalignant systemic disease that would preclude the patient from receiving
study treatment or would prevent required follow-up.

- Sensory/motor neuropathy greater than/equal to grade 2, as defined by the NCI's CTCAE

- Conditions that would prohibit administration of corticosteroids.

- History of hypersensitivity reaction to drugs formulated with polysorbate 80.

- Pregnancy or lactation at the time of study entry. (Note: Pregnancy testing should
be performed according to institutional standards for women of child-bearing

- Use of any investigational agent within 4 weeks prior to enrollment in the study.

- Psychiatric or addictive disorders or other conditions that, in the opinion of the
investigator, would preclude the patient from meeting the study requirements.

Type of Study:


Study Design:

Allocation: Non-Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

Number of Patients With Pathological Complete Response (pCR) in the Breast and Nodes for Patients With HER2-positive LABC Following Neoadjuvant Treatment (Cohort A)

Outcome Description:

The determination of pCR is performed by the local pathologist following examination of tissue (breast and nodes)removed at the time of surgery. The outcome measure is the number of participants with no histologic evidence of invasive tumor cells in the surgical breast specimen, axillary nodes, or SNs identified after neoadjuvant chemotherapy.

Outcome Time Frame:

Assessed at time of surgery on average at 8 months

Safety Issue:


Principal Investigator

Norman Wolmark, MD

Investigator Role:

Principal Investigator

Investigator Affiliation:

NSABP Foundation, Inc.


United States: Food and Drug Administration

Study ID:




Start Date:

May 2007

Completion Date:

May 2014

Related Keywords:

  • Breast Cancer
  • Epirubicin
  • Cyclophosphamide
  • Docetaxel
  • Trastuzumab
  • Bevacizumab
  • Neoadjuvant Therapy
  • HER2
  • Locally Advanced Breast Cancer
  • Adjuvant Therapy
  • Pathologic Stage III Breast Cancer
  • Inflammatory Breast Cancer
  • Breast Neoplasms



University of Iowa Iowa City, Iowa  52242
Rush University Medical Center Chicago, Illinois  60612-3824
Cancer Institute of New Jersey New Brunswick, New Jersey  08901
University of Pittsburgh Pittsburgh, Pennsylvania  15261
Albert Einstein Healthcare Network Philadelphia, Pennsylvania  19141
Baptist Regional Cancer Institute Jacksonville, Florida  32207
Kimmel Cancer Center at Jefferson Philadelphia, Pennsylvania  19107
Kaiser Permanente-Vallejo Vallejo, California  94589
Michigan State University - Breslin Cancer Center East Lansing, Michigan  48824-1313
Mercy Hospital Scranton, Pennsylvania  18501
Aultman Hospital Canton, Ohio  44710
East Carolina University Greenville, North Carolina  27858
NSABP Foundation, Inc. Pittsburgh, Pennsylvania  15212
Clearview Cancer Institute- Huntsville Huntsville, Alabama  35801
Kaiser Permanente-San Diego San Diego, California  92120
CCOP, Colorado Cancer Research Program, Inc. Denver, Colorado  80224
CCOP, Central Illinois Springfield, Illinois  62526
CCOP, Northern Indiana Cancer Research Consortium South Bend, Indiana  46601
NortonHealtcare Inc. Louisville, Kentucky  40202
CCOP, Grand Rapids Clnical Oncology Program Grand Rapids, Michigan  49503
CCOP, Michigan Cancer Research Consortium Grosse Pointe Woods, Michigan  48236
CCOP, Kalamazoo, MI Kalamazoo, Michigan  49007
CCOP, Metro-Minnesota Minneapolis, Minnesota  55416
CCOP, Cancer Research for the Ozarks Springfield, Missouri  65804
University Hospital and Medical Center - SUNY Stonybrook, New York  11794
CCOP, Southeast Cancer Control Consortium Charlotte, North Carolina  28203
Case Western Reserve/University Hospitals-Ireland Cancer Cntr. Cleveland, Ohio  44106
CCOP, Dayton, OH Dayton, Ohio  45429
CCOP, Columbia River Oncology Portland, Oregon  97225
Allegheny General Hospital/Allegheny-Singer Research Institute Pittsburgh, Pennsylvania  15212
CCOP, Upstate Carolina Spartanburg, South Carolina  29303
Joe Arrington Cancer Research & Treatment Center Lubbock, Texas  79410
CCOP, Scott and White Memorial Hospital Temple, Texas  76508
MBCCOP, Virginia Commonwealth University Richmond, Virginia  23298
CCOP, Marshfield Clinic Marshfield, Wisconsin  54449